The osteoporosis is a syndrome which develops a symptom wherein a bone mass per unit volume is unusually decreased without causing any change in the chemical composition (ratio between organic substance and mineral substance) of the ossein per se and physiologically characterized by a decrease in protein, calcium and phosphorus in the bone.
The decrease in bone mass as a symptom includes that caused by physiological aging. Accordingly, the definition of the disease will be a remarkable decrease in bone mass which is greater than that caused by the physiological aging and the manifestation of clinical symptoms such as dorsolumbar pain, pathologic fracture, vertebral deformation and the like.
The osteoporosis proceeds with aging and generally damages vertebra and causes dorsolumbar pain and shortening of the height. In a very advanced case, long bone is also damaged to sometimes cause fracture. The femoral fractures seen in old people are said to be mostly due to senile osteoporosis.
The causes of the osteoporosis are diverse and include abnormal internal secretion inclusive of menopause, nutritional disorder and so on. The vitamin D preparations, calcium preparations, calcitonin preparations, bisphosphonate preparations and so on conventionally used for treating osteoporosis suffer from limitation on administration targets and unconclusive effects. As regards female hormone preparations, its dependable effects are associated with severe side effects such as genital cancer caused by a long-term use of the preparation.
Hence, the development of a therapeutic agent for osteoporosis, having reliable effects and high safety is strongly demanded.
In recent years, thionaphthene-2-carboxylic acid derivative and 3-phenyl-4H-1-benzopyran-4-one derivative (isoflavone derivative) having a completely different chemical structure from the aforementioned preparations have been reported to have bone resorption-inhibitory activity and to be useful as therapeutic agents for treating osteoporosis (A. J. Johannesson et al, Endocrinology, 117, P. 1508, EP-A-135172, EP-A-136569, EP-A-146921, U.S. Pat. No. 4,644,012).
As the derivative having bone resorption-inhibitory activity, (cycloalkylamino)methylenebis(phosphonic acid) derivative (U.S. Pat. No. 4,970,335), heterocyclic bisphosphonic acid derivative (U.S. Pat. No. 4,990,503) and benzofuroquinoline derivative (EP-A-357172) have been reported.
As the compounds having a diazepine skeleton, known are benzodiazepine compounds, thienodiazepine compounds, benzotriazolodiazepine compounds, benzimidazolodiazepine compounds and thienotriazolodiazepine compounds, having antianxiety, sedative and muscle-relaxing actions. Specific examples are bromazepam, clotiazepam, diazepam, flunitrazepam, flurazepam, lorazepam, medazepam, nitrazepam, oxazepam, azinazolam, alprazolam, brotizolam, estazolam, etizolam, midazolam and triazolam.
In addition, certain diazepine compounds such as devazepide and L-365260 are known to have cholecystokinin (CCK) antagonistic action or gastrin antagonistic action (Japanese Patent Unexamined Publication Nos. 63666/1986, 238069/1988 and 223290/1991 and W089/05812).
As the compounds having a platelet activating factor (PAF)-antagonistic action and expected to be an antiasthma agent and a circulatory drug, known are thienotriazolodiazepine compounds such as 4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno[3, 2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 3-(4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a] [1,4]diazepin-2-yl)propionic morpholide, 4-(3-(4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][ 1,4]diazepin-2-yl)propionyl)morpholine, 4-((6-(2-chlorophenyl)-8,9-dihydro-1-methyl-4H,7H-cyclopenta[4,5]thieno-[3 ,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)carbonyl)-morpholine, 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-N,N-dipropyl-4H,7H-cyclopenta[4,5] thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine-8-carboxamide, 6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro -8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine, and optical isomers thereof (Japanese Patent Unexamined Publication Nos. 87623/1986, 87684/1986, 176591/1986, 181282/1987, 240686/1987, 33382/1988, 35574/1988, 197484/1989, 98835/1990, 79185/1989, 79186/1989, 85978/1989, 156982/1989, 256681/1990, 49787/1990, 191281/1990, 243691/1990, 256682/1990, 275883/1990, 286684/1990, 289582/1990, 145437/1991, 215489/1991, 264588/1991, 264589/1991, 66585/1992).
As stated above, the therapeutic agents for osteoporosis so far reported do not necessarily exhibit satisfactory effects and the development of a compound having superior action is awaited.
Accordingly, an object of the present invention is to provide a superior therapeutic agent for osteoporosis. Another object of the present invention is to provide a novel compound to be used as an active ingredient of a therapeutic agent for osteoporosis.
A still another object of the present invention is to provide a method for treating osteoporosis and use for the treatment of osteoporosis.